P1456: EARLY SAFETY AND CLINICAL COURSE OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND MEASURABLE RESIDUAL DISEASE RECEIVING GTA002, AN OFF-THE-SHELF, EX VIVO-CULTURED ALLOGENEIC NK CELL PREPARATION
Authors: M. Heuser, W. Fiedler, A. Block, D. C. de Leeuw, A. van de Loosdrecht, A. Astrid Tschan-Plessl, J. Passweg, A. Kloos, A. Schwarzer, L. Venturini, A. D. Duru, K. Pinkernell, A. Ganser
Journal: HemaSphere (2022)

Background: Measurable residual disease (MRD) is a predictor of adverse prognosis in patients with Acute Myeloid Leukemia (AML). Elimination of MRD in patients having reached complete remission (CR) could therefore improve their long-term outcomes. Aims: In the WiNK trial (NCT04632316), AML patients, who are in CR/CRi with MRD positivity, but are not undergoing allogeneic hematopoietic stem cell transplantation and who have signed informed consent, are treated with an “off-the-shelf” (readily available), allogeneic (unmatched), cryopreserved NK cell preparation (GTA002), which is generated from CD34+ hematopoietic stem and progenitor cells derived from umbilical cord blood. Methods: The WiNK trial is an ongoing, prospective, open-label, single arm, multicenter Phase I/IIa trial to evaluate the safety and efficacy of GTA002. The Phase I portion follows a 3 + 3 dose escalation design with 3 cohorts testing 1, 2 or 3 infusions (dose levels (DL) 1 to 3) with up to 1 x 109 viable NK cells/dose, spaced 4 days apart, resulting in a cumulative dose range of 1 (lowest) to 3 x 109 (highest) viable NK cells. GTA002 is infused after a conditioning regimen of cyclophosphamide (Cy) and fludarabine (Flu) from day -5 to -3 at 300 and 30 mg/m2, respectively, with no subsequent planned antileukemic treatment. MRD is assessed by multiparametric flowcytometry (MRD-MFC) and error corrected next generation sequencing (MRD-NGS), while chimerism analysis is assessed by duplex qPCR. Results: To date, three patients have been treated at DL1 and two at DL2. Median age of all 5 patients was 73 years (range 69 to 81) with an ELN risk category of favorable in one, intermediate in three and adverse in one patient. Infusions with GTA002 were well tolerated at DL1, with no serious adverse events (SAE) or adverse events (AEs) related to the IMP. One SAE Grade (G) 3 febrile neutropenia related to the conditioning was reported, resulting in a protocol change to a lower dose of Cy/Flu. No ICANS, CRS or GvHD was reported. Severe AEs were almost all (8 of 9) related to the conditioning regimen: anemia G3 (2x), leukopenia G4 (2x), neutropenia G3 (1x) and G4 (1x), thrombocytopenia G4 (1x), febrile neutropenia G3 (1x), lactic acidosis G3 (1x). At DL2, no SAE or dose limiting toxicity was reported up to the date of data cut off. At DL1, all three patients achieved changes of their MRD levels with MRD negativity of 9, 1 and 2 months (ongoing) by MRD-MFC. MRD-NGS showed MRD negativity for 6 (NPM1), 4 (PTPN11 clone only, out of 3 clones: PTPN11, IDH2, SRSF2) and 0 months (mutated TP53). At DL1, GTA002 could be detected by chimerism analysis in peripheral blood at levels up to 2.4% with trace amounts present up to 4 weeks after infusion. Summary/Conclusion: GTA002 treatment of AML patients in CR/CRi with MRD was well tolerated with manageable side effects of the conditioning therapy. Even at the lowest dose level, periods of MRD negativity could be documented by MFC and NGS adding to the excitement of the evaluation of allogeneic, off the shelf NK cell-based immunotherapies in hematological malignancies.